Mol Cell Biol. 2016 Nov 28. pii: MCB.00461-16. [Epub ahead of print]

High-fat diet promotes mammary gland myofibroblast differentiation through miR-140 downregulation.

Wolfson B¹, Zhang Y¹, Gernapudi R¹, Duru N¹, Yao Y¹, Lo PK¹, Zhou Q².

Abstract

Human breast adipose tissue is a heterogonous cell population consisting of mature white adipocytes, multipotent mesenchymal stem cells, committed progenitor cells, fibroblasts, endothelial cells, and immune cells. Dependent on external stimulation, adipose derived stem cells differentiate along diverse lineages into adipocytes, chondrocytes, osteoblasts, fibroblasts, and myofibroblasts. It is currently not fully understood how high-fat diet reprograms adipose-derived stem cells into myofibroblasts. In our study, we use regular-diet and high-fat diet induced obesity mouse models to investigate the role of dietary fat on myofibroblast differentiation in the mammary stromal microenvironment. We find that high-fat diet promotes myofibroblast differentiation by decreasing miR-140 expression in mammary adipose tissue through a novel negative feedback loop. Increased TGFβ1 in obese mammary adipose tissue activates SMAD3 signaling, causing phospho-SMAD3 to bind to the miR-140 locus and inhibit miR-140 transcription. This prevents miR-140 from targeting SMAD3 for degradation, resulting in amplified TGFβ1/SMAD3 signaling and miR-140 downregulation dependent myofibroblast differentiation. Using tissue and co-culture models, we find that myofibroblasts and the fibrotic microenvironment created by myofibroblasts impacts the stemness and proliferation of normal ductal epithelial cells and early stage breast cancer invasion and stemness.